[Joe]

There was a study done a few years back in Finland called the FINHER Study. The patients in that study received Herceptin for only 9 weeks and the results were not much different than the larger 12 month or the 24 month HERA Trial.

FinHer Study Finds That Short Course of Herceptin Might Be Effective Against Breast
Cancer Recurrence and Also Limit Heart Damage

A 3-year interim analysis of the FinHer (Finland Herceptin) study, published in the February 23, 2006 issue of the New
England Journal of Medicine, found that adjuvant treatment with docetaxel (Taxotere®) prior to chemotherapy
significantly decreases recurrence in women with node-positive or high-risk node-negative early stage breast cancer
compared to vinorelbine (Navelbine®). A planned subgroup analysis of HER2-positive patients found that adding a nineweek
course of trastuzumab (Herceptin®) to Taxotere or Navelbine prior to chemotherapy also significantly improved
recurrence-free survival.
March 2006
A 3-year interim analysis1 of the FinHer (Finland Herceptin) study, published in the February 23, 2006 issue of the New
England Journal of Medicine, found that adjuvant treatment with docetaxel (Taxotere®) prior to chemotherapy
significantly decreases recurrence in women with node-positive or high-risk node-negative early stage breast cancer
compared to vinorelbine (Navelbine®). A planned subgroup analysis of HER2-positive patients found that adding a nineweek
course of trastuzumab (Herceptin®) to Taxotere or Navelbine prior to chemotherapy also significantly improved
recurrence-free survival.
How was the study done?
This study randomly assigned 1,010 women with node-positive or high-risk node-negative early stage breast cancer to
either 3 cycles of Taxotere or Navelbine, followed by (in both groups) three cycles of fluorouracil, epirubicin, and
cyclophosphamide (FEC). Women who were estrogen-receptor positive and/or progesterone-receptor positive were also
put on Tamoxifen for 5 years following chemotherapy (approximately 72.5% of patients). All women who had a
lumpectomy received adjuvant radiation therapy after chemotherapy (approximately 97% of patients).
There were 232 women with HER2-positive breast cancer (23% of the study population) who were further randomized to
receive either nine weekly infusions of Herceptin or no Herceptin. HER2 expression was scored by
immunohistochemistry (IHC) and HER2/neu gene amplification was confirmed by chromogenic in situ hybridization
(CISH) when IHC findings were scored as 2+ or 3+ (on a scale of 0, 1+, 2+, or 3+).
This is one of several studies looking at Herceptin in addition to chemotherapy in the adjuvant setting. While all reports
from interim analyses of these studies favor the use of Herceptin, the optimal length of treatment with Herceptin has not
been established. This is the first study to report on the effect of a short course of treatment (less than one year) with
Herceptin on patient outcomes.2 Women randomized to Herceptin started their treatment at the same time as Taxotere
or Navelbine. By administering Herceptin before FEC, the authors sought to determine whether this schedule would "limit
cardiotoxicity and maintain efficacy."3 The primary endpoint of this study was recurrence-free survival.4 The authors of
this study plan to release a final analysis of their findings in two years (after five years of follow-up).
The study had a factorial design5 that included the prospective comparison of all HER2-positive patients who were
randomly assigned to receive one of the two chemotherapy regimens described above with or without Herceptin.
Factorial designs can be appropriate and efficient methodologies to answer multiple research questions in prospective
clinical trials. Subgroup analyses in this setting differ from the data mining that occurs when studies 'slice' the population
of participants to analyze the effects of interventions among groups with specific characteristics.6
What were the results?
The preliminary results of this study show that women taking Taxotere experienced a 42% reduction in risk of recurrence
or death4 compared to women taking Navelbine (8.4% versus 14% recurrence rate, or a 5.6% absolute difference), and
a 44% reduction in risk of metastasis (6.6% versus 11.4%, or a 4.8% absolute difference). At this time, there is no
observed significant difference in overall survival between the two groups. Women on Taxotere experienced more
adverse effects7 than those on Navelbine, and as a result the originally scheduled dose of Taxotere had to be lowered
during the course of the study.
Among HER2-positive patients, women who took Herceptin in addition to either Taxotere or Navelbine and
chemotherapy experienced a 58% reduction in risk of recurrence or death compared to those not on Herceptin (10.4%
versus 23.3%, or a12.9% absolute difference), and a 71% reduction in metastasis (7.0% versus 22.4%, or a 15.4%
absolute difference). There was no observed difference in overall survival between these two groups. Women taking
Herceptin did not experience significantly more cardiac events than those not on Herceptin.
What are the implications of this study?
- Taxotere in the Adjuvant Setting
The preliminary findings of this study suggest that Taxotere significantly improves recurrence-free survival compared to

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Navelbine among women with node-positive or high-risk node-negative early stage breast cancer. However, Taxotere
was associated with more toxic effects than Navelbine. A significant number of women in the Taxotere group (almost
40%) were diagnosed with neutropenic fever soon after the trial began, leading the study-monitoring committee to
recommend a 20% dose reduction.
- Herceptin in the Adjuvant Setting
- Length of Herceptin Therapy
This is the first time it has been shown that a short (9 week) course of Herceptin can significantly reduce recurrence
among women with HER2-positive breast cancer. These results add to the increasing body of evidence confirming
Herceptin's efficacy in the adjuvant setting. However, the number of HER2-positive patients randomized within the four
separate arms of this study was small5. It is important that larger studies be conducted in order to determine the optimal
length of therapy with Herceptin. If it can be demonstrated that a shorter course of therapy preserves efficacy, the
implications for patients would be positive in terms of quality of life (by reducing the number of patient visits to the doctor)
and in terms of cost.
- Sequencing of Herceptin Therapy
Prior studies have shown that Herceptin can have a harmful effect on the heart, particularly when combined with certain
chemotherapy regimens8. This study's findings are very interesting because they suggest that administering Herceptin
prior to other therapies with known heart-damaging effects (such as anthracyclines) reduces the risk of adverse cardiac
events3. Further follow-up is necessary in order to assess whether the improved safety of this mode of administration is
preserved over time. Future studies of Herceptin in the adjuvant setting should explore this mode of administration.
The preliminary data from this study on timing of administration of, and length of treatment with, Herceptin are
provocative when considered in the context of other recent findings. Four other studies have shown a substantial
decrease in relapse among women with HER2-positive early breast cancer who received adjuvant Herceptin in addition
to chemotherapy, but the duration of Herceptin use in these trials was much longer (52 weeks on average). Those
studies also showed a substantive increase in the risk of cardiac toxicity in women who took Herceptin with or after
anthracycline-containing chemotherapy regimens. (For an analysis of these four trials, go to NBCCF Analysis on
Adjuvant Herceptin Combined with Chemotherapy in Women with HER2-Positive Early Breast Cancer.)
What are the limitations of this study?
Because this is an interim analysis and the follow-up period is limited there should be caution when interpreting these
results. Since the study's factorial design took into account a prospective analysis of HER2-positive patients who were
randomized to treatment with or without Herceptin, the limitations usually associated with a subgroup analysis are not a
major concern. However, the number of HER2-positive patients (232) between the 4 arms of the Herceptin study makes
it imperative that these findings be confirmed prospectively with a larger study population.
Further follow-up of patients in this study is necessary in order to confirm whether (1) the survival benefits observed for
Taxotere over Navelbine hold up over the long term, (2) the safety benefits observed for short-term adjuvant Herceptin
therapy hold up over the long term, and (3) whether the Taxotere- and Herceptin-containing regimens will have a
significant effect on overall survival in the future.
About NBCCF
NBCCF is a grassroots organization dedicated to ending breast cancer through the power of action and advocacy.
NBCCF's main goals are to increase federal funding for breast cancer research and collaborate with the scientific
community to implement new models of research, improve access to high-quality health care and breast cancer clinical
trials for all women, and expand the influence of breast cancer advocates in all aspects of the breast cancer decision
making process.
Source
Joensuu H, Kellokumpu-Lehtinen PL, Bono P, et al. Adjuvant Docetaxel or Vinorelbine with or without Trastuzumab for
Breast Cancer. N Engl J Med 354(8) 809-20; Feb 23, 2006.
Footnotes
1.An analysis that compares intervention groups at any time before the trial is formally completed. This type of analysis
should be considered preliminary.
2.Previous trials have looked at Herceptin therapy in the adjuvant setting for either one or two years.
3.According to the authors, the principal adverse effects attributable to 12 months of Herceptin therapy given with or after
chemotherapy in the adjuvant setting include heart failure, which occurred in 1.7% to 4.1% of women treated with the

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antibody, and a substantial decrease in the left ventricular ejection fraction (LVEF), which occurred in 10% of Herceptintreated
patients. The risk of cardiac dysfunction with Herceptin treatment increases with the use of anthracyclines.
(Slamon, et al., NEJM 2001; 344:783-92 and Perez, et al., JCO 2004; 22:322-9.)
4.Recurrence-free survival was defined as the time from the date of randomization to the date of detection of local,
distant, or contralateral invasive breast cancer or death, whichever occurred first.
5.In a trial using a factorial design, participants are allocated to one of a certain number of combinations. In the case of
the FinHer study, HER2-positive participants were allocated to (a) Taxotere followed by chemotherapy [n=58], (b)
Navelbine followed by chemotherapy [n=58], (c) Taxotere plus Herceptin followed by chemotherapy [n=54], or (d)
Navelbine plus Herceptin followed by chemotherapy [n=62].
6.Since the effect of an intervention is evaluated within a defined subset of trial participants (e.g. hormone receptor
status), sample sizes within subgroup analyses are often small. Even if the results are statistically significant, these are
considered to be hypothesis-generating and therefore require confirmation in randomized, prospective studies.
7.Taxotere was more commonly associated with neutropenic fever (fever due to infections that develop after an
individual's white blood cells have decreased), stomatitis, alopecia, toxic effects on the skin, nail problems, allergic
reactions, neuropathy, and edema than was Navelbine, which more frequently caused peripheral-vein phlebitis, and
elevation in the serum aspartate aminotransferase level.

8.These studies include the NSABP B-31, NCCTG N-9831, and BCIRG 006 trials.



Regards
Joe